Since the neuropathology of Alzheimer's disease (AD) invariably occurs in individuals with Down Syndrome (DS) before the age of 40, these individuals provide a unique opportunity for studying the location and clinical correlates of brain atrophy. We will study, by magnetic resonance imaging (MRI), brain regions known to become affected by AD in 47 individuals with DS, as compared to 70 normal controls and 20 individuals with fragile X syndrome. We will determine how these MRI measures change longitudinally in order to describe the progression of the brain changes of AD in DS, and their relation to clinical features of dementia. We will test the following hypotheses regarding the development of AD in DS: 1) There is an orderly sequence in the development and spread of the neuropathology of AD (specifically, progressively through the olfactory regions, cingulate cortex and hippocampus, association areas and sensory areas). 2) This sequence can be related to the development of clinical features of dementia in DS. Specifically, particular brain changes must exceed a threshold of severity to result in symptoms; and that individuals with larger brains are relatively resistant to dementia.